Objectives: 1. We are investigating the metabolic pathogenesis of the experimental model of type 2 renal tubular acidosis induced in patients with hereditary fructose intolerance. We have evidence that the reduction of ATP and the accumulation of fructose-1-phosphate induced in the liver, renal cortex and small bowel of these patients is not of itself sufficient to account for the dysfunctions of these organs. In the rat and in the dog, administration of fructose in an amount productve of striking reductions of ATP and inorgaaic phosphate as well as striking accumulation of F-1-P is not associated with demonstrable abnormalities of renal tubular function. 2. We are pursuing the question of the extremely large alkali requirement of infants and children with classic renal tubular acidosis when they are successfully treated with alkali therapy. Their requirement for alkali therapy cannot be explained by the magnitude of their renal bicarbonate wasting. It would appear that the large alkali requirement is a consequence of either increased endogenous production of acid or increased gut loss of base. 3. We have found that in a large group of patients with chronic renal disease, the combination of hyporeninemia and hypoaldosteronism is associated with an acidification defect like that of type 2 (proximal) renal tubular acidosis. The acidification defect is considerably greater than that normally associated with low grade reduction in glomerular filtration rate. It would appear that some of these patients have animpaired capacity to respond to aldosterone i.e., at least with respect to renal acidification.